Effects of brain-selective estradiol on gene expression and female sex behavior

描述（由申请人提供）：对新的和更安全的雌激素疗法（ET）的需求尚未得到满足，以治疗与雌激素水平低或缺乏相关的症状，包括性动机降低、潮热、睡眠障碍、抑郁/焦虑、脑和脊髓创伤、肌萎缩性侧索硬化症和认知功能障碍。目前，只有雌激素单独或与孕激素或雄激素组合可用于治疗这些病症，包括自然或手术绝经。然而，许多妇女不能或不想服用雌激素，因为它们的潜在副作用，其中最关键的是雌激素对子宫和乳房的影响。然而，雌激素不足导致绝经后性欲下降，可能导致女性性欲障碍（FSDD）。目前FSDD的激素疗法使用雌激素和睾酮治疗，但其有效性有限。雌二醇本身可以恢复性欲，如果剂量产生卵泡中期血清雌二醇水平（100- 300 pg/ml）。然而，在这样的剂量下，存在对乳腺癌或子宫癌风险的担忧，因此所有目前的FSDD治疗都使用低雌激素治疗（20 pg/ml）与睾酮结合，而更大量的雌二醇可能会增加治疗效果。在这里，我们研究了一种新的和潜在的安全的雌激素治疗使用10 b，17 b-二羟基雌甾1，4二烯-3-酮（DHED），以恢复大鼠和猴模型的性感受性和性动机。DHED是雌二醇的非活性前体;它不与雌二醇受体结合，因此在其天然形式下不产生雌激素效应。然而，一种酶将DHED转化为雌二醇。我们的初步证据表明，这种酶只在中枢神经系统中表达，因此可能使DHED成为17 b-雌二醇（E2）的脑选择性前药。穿过血脑屏障的DHED在脑外是不活跃的，但会将有效量的E2递送到脑内。 大脑我们建议使用性行为作为模型雌激素反应系统，以测试DHED的潜在治疗效果。使用连续的DHED和孕酮治疗在切除卵巢的雌性大鼠中诱导脊柱前凸将测试DHED的中枢活性。然后，我们将使用雌性性启动的卵巢切除猴子模型来测试DHED在增加性欲方面的功效。Prokai博士将为本项目合成DHED，并进行DHED转化为E2的体内研究。Merchenthaler博士的实验室将研究急性或慢性DHED治疗后雌二醇诱导的大脑和外周基因表达，并研究DHED激活雌性大鼠性感受性的能力。Wallen博士的实验室将在DHED治疗期间进行雌性恒河猴性启动的研究。来自低雌激素条件的啮齿动物模型的初步数据显示，DHED是E2的脑选择性生物前体，并且可能是由于缺乏雌激素（卵巢切除术）或低水平雌激素（绝经）而引起的条件的安全有效的治疗。如果成功，这些研究将革命性地治疗临床问题所造成的雌激素水平低下的条件。

DESCRIPTION (provided by applicant): There is an unmet need for new and safer estrogen therapies (ET) to treat the symptoms associated with low levels or a lack of estrogens, including decreased sexual motivation, hot flushes, sleep disorders, depression/anxiety, brain and spinal cord trauma, amyotrophic lateral sclerosis, and cognitive dysfunction. Currently only estrogens alone or in combination with progestins or androgens are available to treat these conditions, including natural or surgical menopause. However, many women cannot or do not want to take estrogens because of their potential side effects, the most critical of which are the effects of estrogen on the uterus and the breast. However, estrogen insufficiency contributes to post-menopausal decline in sexual desire that can lead to female sexual desire disorder (FSDD). Current hormonal therapies for FSDD use treatment with an estrogen and testosterone, but their effectiveness is limited. Estradiol by itself can reinstate sexual desire if given at dosages that produce midfollicular serum estradiol levels (100-300pg/ml). However, at such dosages there are concerns about the risk of breast or uterine cancer, thus all current FSDD treatments use hypoestrogenic treatment (20pg/ml) in conjunction with testosterone when larger amounts of estradiol would likely increase treatment effectiveness. Here we investigate a novel and potentially safe estrogen therapy using 10b,17b-dihydroxyestra 1,4 dien-3-one (DHED) to reinstate sexual receptivity and sexual motivation in rat and monkey models. DHED is an inactive precursor of estradiol; it does not bind to estradiol receptors and thus produces no estrogenic effects in its native form. However, an enzyme converts DHED to estradiol. Our preliminary evidence suggests that this enzyme is only expressed in the CNS thus potentially making DHED a brain-selective prodrug for 17b-estradiol (E2). DHED, which crosses the blood brain barrier, would be inactive outside of the brain, but would deliver effective amounts of E2 to the brain. We propose to use sexual behavior as a model estrogen-responsive system with which to test DHED's potential therapeutic effects. Induction of lordosis in ovariectomized females rats using a sequential DHED and progesterone treatment will test the central activity of DHED. We will then use an ovariectomized monkey model of female sexual initiation to test DHED's efficacy in increasing sexual desire. Dr. Prokai will synthesize DHED for this project and undertake in vivo studies on conversion of DHED to E2. Dr. Merchenthaler's lab will investigate estradiol induced gene expression in the brain and periphery after acute or chronic DHED treatment and investigate DHED's capacity to active female rat sexual receptivity. Dr. Wallen's lab will undertake studies of female rhesus monkey sexual initiation during DHED treatment. Preliminary data from rodent models of hypoestrogenic conditions show that DHED is a brain-selective bioprecursor produg for E2, and is likely to be a safe and effective treatment of conditions due to the lack of estrogens (ovariectomy) or low levels of estrogens (menopause). If successful these studies will revolutionize the treatment of clinical problems resulting from hypoestrogenic conditions.